Crohn disease (CD) is a complex disease involving both genetic and environmental factors. We propose that a specific form of CD can be defined based on Paneth cell function. Of the 150 susceptibility alleles that are associated with this disease, we have previously identified two genes with coding mutations that are associated with abnormal Paneth cell function. These genes are NOD2 and ATG16L1, which have previously been proposed to be functionally linked in other cell types. Our previous work studying the role of Atg16L1 in mouse and mutations in ATG16L1 in CD patients has shown that Paneth cells are targeted by loss of function of this gene and that specific microbes could trigger this defect. We have developed new tools to evaluate the role of environmental triggers including the ability to robustly culture primary intestinal epithelial cells from endoscopic biopsies. The data generated the current proposal and we now propose to utilize the substantial resources of the NIDDK IBD Genetics Research Consortium. In three aims, we will 1) Define a pathway(s) driven by additional CD susceptibility alleles that drive Paneth cell malfunction, 2) Determine the environmental trigger of ATG16L1 T300A and 3) Determine if Paneth cell phenotypes are durable or require constant stimulation. If successful, this project should define a subtype of Crohn's disease and provide biomarkers in the stool and tissue and eventually novel therapeutic targets.